1,4 benzodiazepine-2-ones having a carboxylic acid ester or amide group in the 3-position



J. scum" 3,516,988

I oxvuc ACID ESTER OR AIIDB GROUP IN THE .S-POSITIOH 1.4.aanzonzAzsrms-z-ouns mwnm A cans Original F1106. June 14. 1965 am MN ONv x unnal 2m v V kncan oo I'Wenior use SChmiH United States Patent3,516,988 1,4 BENZODlAZEPINE-Z-ONES HAVING A CAR- BOXYLIC ACID ESTER ORAMIDE GROUP IN THE 3-POSITION Josef Schmitt, 6 Rue Sentier des Garennes,Val-de-Marne, LHay-les-Roses, France Continuation of application Ser.No. 463,613, June 14, 1965. This application Feb. 19, 1968, Ser. No.706,713 Claims priority, application France, June 15, 1964, 978,360;Apr. 12, 1965, 12,886 Int. Cl. C07d 53/06 US. Cl. 26239.3 15 ClaimsABSTRACT OF THE DISCLOSURE Novel benzodiazepine having the formula inwhich R is a hydrogen or halogen atom or a trifluoromethyl, lower alkyl,lower alkoxy, nitro or amino group, R is a furyl, a thienyl, cyclohexyl,a lower alkyl group or a phenyl group which may be substituted by ahalogen atom or by a trifluoromethyl, nitro, lower alkoxy or lower alkylgroup, and R is a hydrogen atom or a lower alkyl group, and R is a lowercarbalkoxy, carbamoyl, an N- loweralkylcarbamoyl, anN,N-diloweralkylcarbamoyl, an N- (diloweralkylaminoalkyl) carbamoyl, agroup having the formulaCOOCat in which Cat is a cation of an alkalimetal or a semication of an alkaline earth metal are prepared bytreating an ortho-aminoarylketimine having the formula in which R R Rand R are as defined above and R is a lower alkyl group or, when R; is acarbamoyl or COOCat group, a cation of an alkali metal or semication ofan alkaline earth metal, but excluding the case in which R; is COOCatand R is "Cat, with an anhydrous lower aliphatic acid or with ananhydrous mineral acid, or, when R, is -COOCat and R is CAT, with adilute aqueous solution of an acid salt, in particular potassiumdihydrogen orthophosphate, in substantially equimolar proportion or witha weak acid.

This application is a continuation of Ser. No. 463,613, filed June 14,1965, now abandoned.

This invention relates to pharmacologically useful materials which areortho-aminoarylketimines and, in their cyclic form, benzodiazepines. Theinvention consists in certain new compounds as well as in the processesfor the production thereof.

The ortho-aminoaryl ketimines have, in one tautomeric form, the generalformula NHRa RI- CR2=NR in which R is a hydrogen atom or a group havingthe general formula R is a hydrogen or halogen atom or atrifluoromethyl, lower alkyl, lower alkoxy, nitro or amino group, R is afuryl, a thienyl, a lower cycloalkyl, a lower alkyl group or a phenylgroup which may be substituted by a halogen atom or by atrifluoromethyl, nitro, lower alkoxy or lower alkyl group and R is ahydrogen atom or a lower alkyl group, R, is a hydrogen atom, a lowercarbalkoxy, a carbamoyl, Nloweralkylcarbamoyl, anN,Ndiloweralkylcarbamoyl, an N(diloweralkylaminoalkyl) carbamoyl, loweralkyl or substituted lower alkyl group, a group having the generalformula COOCat in which Cat is a cation of an alkali metal or semicationof an alkaline earth metal or a group which, in a naturally occurringu-aminocarboxylic acid, is linked to the carbon atom carrying thea-amino group, and R is a lower alkyl group or, when R, is a carbamoylor -COOCat group, a cation of an alkali metal or semication of analkaline earth metal. When R is a halogen atom it is preferably achlorine atom. When R is a lower cycloalkyl group it is preferably acyclohexyl group.

The substituted benzodiazepines, in accordance with the invention, have,in one tautomeric form, the general formula in which R R and R are asdefined above and R is a lower carbalkoxy, a carbamoyl, anN-loweralkylcarbamoyl, an N,N-diloweralkylcarbamoyl, anN(diloweralkylaminoalkyl) carbamoyl, a group having the general formulaCOOCat in which Cat is a cation of an alkali metal or a semication of analkaline earth metal or a group which, in a naturally occurringa-aminocarboxylic acid, is linked to the carbon atom carrying thea-amino group.

In the present specification the alkyl groups, including those presentin alkoxy and aralkyl groups have 1 to 7 carbon atoms in a straight orbranched chain; for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertiary butyl, amyl and hexyl groups.

These products corresponding to Formula I may be prepared by a reactionfor which the starting material is an ortho-amino aryl ketiminerepresented by the general Formula III in which the groups R R and R areas above defined.

These ortho-aminoaryl ketimines may be obtained according to the presentinvention by reacting an orthoaminobenzonitrile having the substituentR, with an excess of magnesium alkyl halide or magnesium aryl halide RMgX, in which R is as above defined and X is a halogen atom,particularly bromine. A substantial excess of the Grignard reagent R MgXis used, preferably about 3 to 4 molecules per molecule ofortho-aminobenzonitrile used. The process may be carried out inanhydrous ethyl ether and the starting materials allowed to react inboiling solvent for up to about 15 hours. After cooling, the magnesiumcomplex is decomposed with an aqueous ammonium chloride solution and thesolvent evaporated. The ortho-amino aryl ketimine crystallises in mostcases spontaneously and may be purified by recrystallisation from asuitable solvent, in particular from a hydrocarbon such as hexane orcyclohexane.

The ortho-amino aryl ketimines are thus obtained in the form of paleyellow, well defined crystalline compounds. The yield is generally high,frequently of the order of to The infrared spectra of these compoundsagree with the structure indicated and is, moreover, confirmed byelementary analysis. The compounds have, among others, two bandscharacteristic of the vibrational frequency of the N-H bond: a fine.line in the region of 3480 cm. (absent if the aromatic amine issecondary) and a wide band at 3270-3300 cm. due to the NH of the imineand to the chelated NH of the NH, (or NHR) group; moreover, the infraredspectra show two bands of vibration in the region of 1600 cm."(1610-1580 cm.- due to the aromatic C=C conjugated to C=N.

Table I sets out certain imines having the general Formula III which arenew and which may be prepared as indicated in the examples givenhereinafter.

TABLE I NHR;

R1 ?=NH R2 R Example CuHis H 1 CnHs CH3 2 CaHs H 3 CoHn (eyclohexyl) H 411-04119 H The substituted imines having the general Formula I (with theexception of the salts of the carboxylic derivatives) may be preparedfrom ortho-amino aryl ketimines (III) and an ester of an a-aminoaceticacid in which R, is as above defined other than -COOCat. In the simplestcase, this a-aminoacetic acid ester may be an ester of glycine but itmay also be an ester of a naturally occurring optically active orracemic a-amino acid such as alanine, leucine or methionine; lastly, theester may be a derivative of aminomalonic acid, in particular dimethylor diethyl aminomalonate.

These esters may be used in the form of bases but preferably in the formof salts which are easier to deal with than the base, especially thehydrochloride. The reaction is accompanied by liberation of ammonia,either free or combined in the form of a salt according to the equationgiven below (in which Alk denotes a lower alkyl group):

The reaction may be carried out in a solvent which is inert with respectto the imine III, in particular a lower aliphatic alcohol or ahydrocarbon such as benzene or toluene, and at a temperature betweenroom temperature and the reflux temperature of the diluent. The reactiontime may vary between 1 and 12 hours; the higher the temperatureemployed, the shorter will be the reaction time. In certain cases, thereaction product separates spontaneously from the alcoholic solution atroom temperature. Nevertheless, it is advantageous to evaporate off thesolvent when the reaction is terminated, extract the product with aninert solvent and isolate it by crystallisation from a suitable solvent.

The substituted imines I which have an ester function are obtained inthe form of pale yellow products, in most cases crystalline butsometimes in the form of oils. Their structure is determined byelementary analysis, study of their infrared spectra and the results ofacid hydrolysis.

As could be expected theoretically, the substituted imines (I) can existin two stereoisomeric forms one of which, generally obtained in largerquantity, is characterised by an intramolecular NH hydrogen bond betweena hydrogen on the amino group and the nitrogen of the imino group(forming a chelate ring). In two of the appended examples (see Examples6 and 7) these two forms were isolated by fractional crystallisation; inthe other cases, the product isolated was generally a crystallineproduct corresponding to the chelate form.

The infrared spectra, determined in methylene chloride, of the chelateforms have a vibration band of the NH group in the region of 3480 cm? (afine line would not be seen in the case of a secondary amine) and a Wideband at 31503300 cm.- due to the chelate bond NH of the group NH; (orNI-I-R); in the region of 1730-1740 cm.- a vibration band of C=O of theester radical; in the region of 16101620 cm? a band of the aromatic C=C(and C=N-); at 1200-1180 cm.- a COC band (ester) shifted to 1220 cm. inthe case of malonic esters. The non-chelate forms differ from the aboveby the existence of a doublet formed by two fine lines due to the NHvibrations of NH;, (a single line at 3400 cm.- in the case of secondaryamines) and by the absence of absorption bands between 3150 and 3300cm.-

Investigation of the hydrolysis of imines (I) by a strong mineral acidparticularly hydrochloric acid leads to different results according tothe presence or absence of an internal hydrogen bond: if there is nochelation, the action of hydrochloric acid leads to the formation of thecorresponding ortho-amino ketone due to severing of the imine bond; inthe case of internal chelation, the imino bond is not severed and thecorresponding benzodiazepine is formed, the configuration of which ismoreover favourable to cyclisation.

In Table II, a certain number of substituted imines are shown whichcorrespond to the general Formula I above in which R is an alkyl group;these imines are all new.

TABLE II NHR;

/O R 1- -(I3=N- C H- C R: R4 0 R4 N0- R1 R R R4 R5 Example 4292 GEL...Cl C5H5 H H C2115 6 Cl Cal I5 CH3 H 2115 7 CaH5 H COOCzH C 8 C0115 CH300002115 C211 9 CuHr, H H 1H5 10 03115 H COOC2H5 C2H5 l1 C5115 H H 211512 n--C4Ho H H C H5 13 1 Isolated in two stereoisomeric crystalllnoforms.

We have found that the action of an anhydrous lower aliphatic acid, inparticular glacial acetic acid, on either of the two stereoisomericforms of the substituted imines (I) as well as on mixtures of these twoforms leads almost exclusively to the corresponding benzodiazepine.Heating for from several minutes to one hour is desirable; after removalof the acid reagent in vacuo and dilution with a suitable solvent, inparticular diethyl ether or diisopropyl ether, the benzodiazepinederivative is obtained directly in crystalline state.

Thus 7-chloro-5-phenyl-2,3-dihydro 1H-benzo[f]-1,4- diazepine (namedhereinafter compound A) which has already been described by L. H.Sternbach and E. Reeder (Journal of Organic Chemistry 1961, volume 26,page 4936) may be prepared in two stages, giving an overall yield of80%, from the unsubstituted imine 4356 CB without having to separate thetwo stereoisomeric forms of the intermediate substituted imine 4292 CB;the N- methyl derivative (B) of compound A, which is already known (seeabove reference) is obtained in a practically quantitative yield bysubjecting the substituted imine 4361 CB for several minutes to theaction of acetic acid.

Employing the same technique, the derivatives of compound A substitutedon the 3 carbon atoms are obtained. For this purpose, it is sufiicientfirst to react, according to the process of the invention, the freeimine 4356 CB with the hydrochloride of a suitably selected m-amino acidester without isolating the intermediate substituted imine and proceedwith the acetic acid treatment in question. For example, using thehydrochlorides of analine, leucine and methionine as reagents, oneobtains the 3-methyl, 3- isobutyl and 3-methylthioethyl derivativesrespectively of 7-chloro-5-phenyl-2-oxo-2,3-dihydro 1H-benzo[f]-1,4-diazepine (compounds C, D, E). The yields vary but are always muchhigher than those indicated in the chemical literature for the samesubstances (Sternbach, Fryer, Metlesics, Reeder, Sach, Saucy andStempel, Journal of Organic Chemistry 1962, volume 27, page 3788).

This method has been extended to the preparation of new benzodiazepinescarrying a carbalkoxy group on the 3-carbon atom. For this purpose, itis suflicient to treat malonic acid derivatives of products of type (I)such as those indicated in Table II with an aliphatic acid; thesederivatives, obtained by the action of a free imine of Formula III onthe hydrochloride of an alkyl aminomalonate, may or may not be isolated.However, the yield is particularly high when crystalline substitutedimines (I) are reacted in acetic acid.

We have found an advantageous modification for the preparation ofbenzodiazepines (II) without isolation of the substituted imines (I),which modification is particularly recommended in cases in which thegroup R in the general Formula II denotes a phenyl or substituted phenylgroup, R is a hydrogen atom and R is a carbalkoxy group. Although thesesubstances are easily obtained by the process described above, startingfrom ketimines III such as 4356 CB the yields are somewhat low and theresults are diflicult to reproduce if the quantity of reactants used isincreased, Whilst complete purification of the products bycrystallisation is, in some cases, laborious. According to thismodification, the substituted imine (I) such as 4292 CB is formed by theaction of the hydrochloride of an alkyl amino-malonate on the free imine(III) such as 4356 CB, the reaction being carried out in a hydrocarbonsolvent, preferably benzene or toluene, whilst hydrogen chloride gas ispassed through the reaction medium to control the cyclisation withoutfirst isolating the intermediate compound. The resulting benzodiazepinederivative such as 4279 CB is then isolated in the form of thehydrochloride which can subsequently be decomposed into practically purebenzodiazepine.

This improvement is suitable for the preparation of otherbenzodiazepines having the general Formula II, in particular thosementioned in Table III which may or may not be substituted on the carbonatom in position 3 in the heterocycle. All that is necesssary is toreplace the hydrochloride of ethyl aminomalonate by the hydrochloride ofan alkyl glycine such as ethyl glycine which may or may not besubstituted on the methylenic carbon atom.

This procedure is recommended for the synthesis in large quantities ofcompound 4190 CB (Formula II where R ==cyclohexyl, R =H, R =H). The useof substituted or unsubstituted amino-malonic esters or amino-aceticesters is not limited to ethyl ester.

The structure of the new carbalkoxy-3-benzo-diazepines (II) is obtainednot only from the elementary analysis of these compounds but also from astudy of their infrared spectra and the results of hydrolysis. Theinfrared spectra of 3-carbalkoxy benzodiazepine (II) dissolved inmethylene chloride have the following features. Vibration bands of theNH bond of the lactam group without substituent (if this is the case):namely a fine line (free NH) in the region of 3400 cm." and a wide band(attached N-H) in the region of 3200 cmr In potassium bromide, theabsorption due to NH is often more complex and may result in thepresence of various bands between 3100 and 3400 cm.- characteristicbands of the ester group at 1730-1755 C=O) and in the region of 1200cm.(COC); a characteristic band of a secondary amide at 1660-1700 cm.-(absence of the amide II band between 1510 and 1550 cm. a band at 1590-1610 cm.- (aromatic C=C and C=N) flanked by a less intense band at15604580 cm.- for compounds having two phenyl groups conjugated to C=N.

The treatment of 3-carbalkoxy benzodiazepines (II) with a saponifyingagent (for example, an alkali metal hydroxide, preferably aqueous oralcoholic potash) and then with a dilute acid reagent (for example,acetic acid), gives rise to hydrolysis and decarboxylation and finallyleads to benzodiazepines which are unsubstituted on the 3-carbon atomand, for example, to com-pound A if compound 4279 CB is put into thereaction, which completely demonstrates the structure proposed. By thetreatment of the 3-carbalkoxy benzodiazepines (II) with an alkali suchas aqueous or alcoholic potash, then with an alkylating agent such asdimethyl sulphate and thereafter with a dilute acid such as acetic acid,there are obtained the lalkylbenzodiazepines, for example, compound B(diazepam) when compound 4279 CB is used. Instead of using the3-carbalkoxy benzodiazepines (II) the di-salts obtainable by the actionof an alkali on the compounds (II) may be treated with an alkylatingagent. The action of ammonia or of a primary or secondary amine at roomtemperature in a suitable solvent such as methanol converts the3-carbalkoxybenzodiazepines (II) into benzodiazepines carrying an amidefunction, with or without substituent, in the 3-position.

Nitration of the benzodiazepine derivative 4352 CB in sulphuric acidleads to aromatic derivatives nitrated in the 7-position (cf. 4353 CB);the structure is determined by elementary analysis, by the infraredspectrum (nitro bands at 1530 and 1350 cm. in potassium bromide) and byits hydrolysis accompanied by decarboxylation which leads to7-nitro-phenyl-2, 3-dihydrolH-benzo [f] l ,4-dia- Zepine which isalready known and has been described by Sternbach, Fryer, Keller,Metlesics, Sach and Steiger in Journal of Medicinal Chemistry 1963,volume 6, page 261.

Reduction of the nitro derivative e.g. 4353 CB, for example by catalyticmeans, leads to the corresponding amono compound carrying a 7-aminogroup (of. 4354 CE).

The 3-carbalkoxybenzodiazepines (II) generally have a higher meltingpoint than the corresponding benzodiazepines which are unsubstituted onthe 3-carbon atom; their solubility in organic solvents is relativelyslight.

Table III indicates a certain number of new benzodiazepines (thoseindicated by a number) carrying a substituent in the 3-position andobtainable by the process of the invention.

TABLE III CH-R4 R R R Example C 11 H H 14, 15 and 16. CaH CH: 11 16 and55. C5H5 H CH: 17. C6115 H CH2CH(CH3)2 18. CaH5 H CH2CH2-SCH3 19. C511511 COOC2H5 20, Zl 111d 49 05115 H COOCII; 22. C 11 CH3 COOCzH5 23.Cal-I5 H CONH2 24. 0 H; II CONH-CII; 25. C511 H CON(CII3)2 26. C 11 HCONHCH2CHzN(C2H5)2 27. C5115 11 C00 02115 28 and 50 C 11 H II 20. Cells11 COCO/2H5 30. C5I-I H COOC H 31. C H I'I 00002115 32. Cal-I11(cyclohexyl) H H 33 and 51 Cal-Iii (cyclohexyl) H COOCZII5 54.

With a view to obtaining products in a convenient water-soluble form forpharmacodynamic studies and clinical use, we have saponified3-carbalkoxybenzodiazepines (II) with an alkali metal hydroxide,preferably potassium hydroxide, in an alcoholic medium. In every case,the di-metal salt of the dibasic acid is obtained in accordance with theequation given below:

Thus, saponification of the free ester group is accompanied by openingof the benzodiazepine ring at the position of the lactam function.

This reaction may be compared with the conversion of7-chloro-5-phenyl-2-oxo-2,3-dihydro-lH-benzo[f]-1,4- diazepine into thecorresponding monosodium salt by the action of a sodium hydroxidesolution as described by Bell, Sulkowski, Gochman and Childress inJournal of Organic Chemistry, 1962, volume 27, pages 562 to 566.

The infra red spectra of compounds IV-A, determined in potassiumbromide, agree with the structure, in particular the absence of the C=Obands (amide, acid or ester) between 1650 and 1750 cm.- moreover, theyshow among other things a very wide and intense absorption band in theregion of 3400 cm.- (vibrational frequencies of NH of highly chelated NHand a wide and complex absorption in the region of 16001550 cm."

(aromatic C=C C=N, C=O of carboxylate ions).

For ease of manipulation, it is best to work in ethyl alcohol; thetemperature should be between room temperature and the boiling point.The purest products are obtained by operating at room temperature. Thereaction is accompanied by a transient yellow discoloration. For rapiddiscoloration, it is advisable to use at least three equivalents ofpotassium hydroxide. The yield of the dipotassium salt is practicallyquantitative. These dimetal salts (IV-A), a number of which are given inTable IV below, are colourless powders (with the exception of the nitroand amino derivatives which are yellow), very soluble in water andstrongly alkaline in reastion. On acidification, the aqueous solutionsgive rise to the corresponding benzodiazepines unsubstituted on the3-carbon atom: thus the compound 4306 CB becomes benzodiazepine A.

The same salts (IV-A) can be obtained by saponification of imines havinga double ester function of type I according to the reaction indicatedbelow:

The infra-red spectra of the dipotassium salts thus prepared arepractically identical with those of the corresponding salts prepared byopening of the benzodiazepine ring. Moreover, the aqueous solutions ofthe dipotassiurn salts (prepared by either one or the other method) whentreated with dilute hydrochloric acid undergo decarboxylation andcyclisation to give the same benzodiazepine derivative; for example,4306 CB obtained by either one or the other of the two methods givesrise as a result of this treatment to the benzodiazepine compound (A) ofTable III.

Lastly, in the case of compound 4306 CB, pharmacodynamic studies confirmthe identity of the products obtained by the two methods.

As regards Formula IV-A, it should be remarked that the analyticalresults obtained, which will be discused below, are more easilyexplained if one assumes a ring structure such as IV-B or IVC instead ofthe structure IV-A for the compounds considered.

Analytical studies have been carried out especially on compound 4306 CB(compound IV in which R =Cl, 2= e 5 3= Even after prolonged drying ofthis substance at 50 C. under a high vacuum, the products obtained stillcontain approximately of the solvent (10% aqueous ethyl alcohol) inwhich the preparation was carried out.

To determine the quantity of ethyl alcohol, the substance underinvestigation is dissolved in water and the solution obtained isdistilled; the distillate is oxidised with nitrochrome reagent and theexcess reagent is titrated with a solution of ferrocyanide in thepresence of diphenylbenzidine.

To determine the quantity of water, the Karl Fischer method cannot beused owing to the strong basicity of the product, and therefore theproduct is suspended in xylene and water is driven oif as an azeotropicmixture.

The determinations of ethyl alcohol and water carried out as indicatedabove show that, in addition to the 10% of solvent retained, the productcan liberate by azeotropic distillation one molecule of water, which isnot easily explained, if one assumes the structure IV-B or IV-C.

Elementary analysis of the product dried at 50 0., taking into accountthe quantity of solvent of crystallisation present, agrees with thevalues calculated for one of the three Formulae IV-A, IV-B or IV-C,which are identical in their empirical formulae.

Determination of the basic functions of the molecule yields interestingresults especially if, for example, one compares the potentiometricdiagrams obtained for 4306 CB, for the potassium salt of(7-chloro-5-phenyl-2-oxo- 2,3-dihydro 1H-benzo[f]-1,4-diazepine)3-carboxylic acid (4311 CB) and for 7-chloro-5-phenyl-2-oxo-2,3-dihydro1H-benzo[f] 1,4-diazepine (indicated by the reference A above and inExamples 14 and 15).

In an anhydrous medium consisting of a mixture of chloroform (3 vols.)and acetic acid (1 vol.), titration with perchloric acid in acetic acidsolution gives the results shown in the accompanying graph:

For compound 4306 CB (continuous line curve) a first jump in potentialwith an equivalent point located at 370 mv. and a second jump inpotential with an equivalent point located at 600 mv., the total volumeof titrating agent added to reach the second equivalent point being 1.5times the volume added in order to reach the first point.

For compound 4311 CB (discontinuous curve), a first jump in potentialwith an equivalent point located at 360 mv. and a second potential jumpwith an equivalent point located at -590 mv., the volume added in orderto reach the second equivalent point being twice the volume added toreach the first point;

For compound (A) (dotted line) a jump in potential with equivalent pointsituated at 580 mv.

From these experimental data and the known formulae of compound 4311 CBand compound (A), it is obvious that the second jump in potentialobtained in the titration of compound 4306 CB corresponds toneutralisation of the imine function and that the first corresponds toneutralisation of the two other functions, namely:

If one adopts the cyclic Formula IV-B or IV-C, the alcoholic (or enolic)and caboxylic functions; or

If one adopts Formula IV-A, one of the carboxylic acid functions and theamino group, assuming that the second carboxylic function has too low apK value to be determined owing to its proximity to the first carboxylicacid function.

Protometric determination in an anhydrous medium would thus not appearto be suitable for distinguishing between the possible structures. Infact, the result in an aqueous medium rather tends to favour a ringstructure; if this procedure is adopted, it is not possible to carry outthe determination below pH 7 owing to the precipitation of compound 4311CB and compound (A); only functions corresponding to high pK values canbe determined in this way. Compound 4306 CB determined in an aqueousmedium by means of hydrochloric acid has an equivalent point at pH 9.5,which could be attributed to an alcoholic (or enolic) function but lesseasily to one of the functions of the isomer IV-A.

The possibility should not be excluded that under the operatingconditions, the compound 4306 CB used in these tests will assume one ofthe isomeric forms in preference to another. Prolonged heating of thisparticular compound in the solid state at C. seems to favour theformation of the IV-A isomer, as indicated by the protometricdetermination in an aqueous medium, in addition to some alteration ofthe product.

Lastly, it is to be noted that the infra-red spectra of compounds oftype IVA, IVB or IVC and in particular of 4306 CB and 4335 CB arecompatible with the three formulae proposed.

The invention is not in any way limited to a particular representativeformula among the group of Formulae IV-A, IV-B and IV-C.

Table IV gives by way of example some dipotassium salts preparedaccording to the process of the invention.

TABLE IV.FORMULA IVA, IVB OR IVC R2 R Example CBH5 H 35,36 and 52. CnHsCH3 37 and 38. 06115 H 39.

C6H H 41 and 53 OBI-I5 H 2.

1 The disodium salt and the calcium salt were also prepared, the latter(4372 CB; Example 44) by double decomposition from the dipotassium salt.

By carrying out a reaction under the conditions just described, compound4348 CB, which has an amide group in the 3-position, gives rise to thecorresponding carboxylic derivatives in which the initial amide group ispreserved.

(4349 CB; example 43) We have further found that the dimetatl salts suchas those given in Table IV, may, under very accurate conditions, beconverted into benzodiazepine derivatives (V) carrying on the 3-carbonatom a carboxylic acid function salified by the original cation.

Compound having the general Formula IV-A, IV-B or IV-C R I II To bringabout this reaction, it is sufiicient to treat an aqueous solution ofthe product used with a slightly acid reagent at room temperature (thatis to say an amount of acid which is just sufficiently strong toliberate one of the two carboxylic functions), preferably potassiumdihydrogen phosphate or carbon dioxide. The monopotassium salts (V) as arule crystallise readily provided crystallisation is carried out in asufiiciently concentrated solution since they are less soluble in waterthan the compounds (IV) from which they are derived. They are thereforeobtainable in a high yield.

Their formula having been established by elementary analysis, theirstructure is obtained from the study of their infra-red spectra andtheir chemical properties. The infra-red spectrac (determined inpotassium bromide) agree with the structure (V) and show, among otherthings and in contradistinction to compounds (IV), a strong band in theregion of 1690 cm.- due to the C O of the cyclic amide; also to be notedis the absence of the amide II band between 1510 and 1550 cm." which ischaracteristic of non-cyclic secondary amides. Only the nitro group, ifpresent, gives a band in this region. Moreover, the vibration of the NHbond of the lactam group manifests itself by two very wide bands in theregions of 3400 cm.- and 3100 cmr Lastly, an intense and complex band inthe region of 1600-1620 cm.- may be attributed to the vibrations of thearomatic C=C and of the C=N and of the C=O of the carboxyl ion.

Aqueous solutions of compounds V generally have a pH in the neutralregion. Products V are less stable in aqueous solution than thecompounds having two carboxyl groups from which they are derived. Theaqueous solutions liberate the corresponding benzodiazepine derivativesunsubstituted on the 3-carbon atom after standing for several hours atroom temperature or rapidly upon boiling or in the presence of aceticacid at or above room temperature.

Several potassium benzodiazepine 3-carboxylates (V) are shown in Table Vto illustrate this aspect of the invention.

It; Example CaHs CaHs C6H5 (2-amino-5-chlorophenyl -phenyl-methane-imine(43 5 6 CB A solution of 228.7 g. (1.5 mols) ofZ-amino-S-chlorobenzonitrile in 1800 ml. of dry ether is added slowly inthe course of about 3.5 hours to a solution of phenyl magnesium bromideprepared from 109 g. (4.5 gram atoms) of magnesium turnings and 848 g.(5.4 mols) of bromobenzene in 3600 ml. of anhydrous ether, and themixture then heated under reflux for 15 hours.

The complex is decomposed by stirring the reaction mixture into asolution prepared from 500 g. of ammonium chloride in 2000 ml. of waterto which 3 kg. of crushed ice have been added. After extraction andwashing, the ether is evaporated in vacuo at 40 C. The oily residue istaken up in 500 ml. of petroleum ether and left to crystallise bycooling at 20 C. The yellowish crystals formed are dried (309 g.) M.Pt.74 C.; yield: 92%.

EXAMPLE 2 (2-methylamino-5 -chlorophenyl) -phenyl-methane-imine (43 57CB Using the method described in Example 1 but replacing2-amino-5-chlorobenzonitrile by an equimolecular quantity of2-methylamino-5-chlorobenzonitrile, compound 4357 CB is obtained in ayield of 61%: yellowish crystals; M.Pt. 97 C. (hexane).

EXAMPLE 3 (Z-aminophenyl)-phenyl-methane-imine (4358 CB) Proceeding asin Example 1 but replacing the 2-amlno- S-chloro-benzonitrile by anequimolecular quantity of 2-amino-benzonitrile, this compound isobtained in a yield of about of crude product. Yellowish crystals areobtained; M.Pt. 48 C. (isopropyl ether).

EXAMPLE 4 Cyclohexyl- 2-amino-5-chlorophenyl -methane-imine (43 5 9 CBProceeding as in Example 1 but replacing the bromobenzene by theequimolecular quantity of bromocyclohexane, this compound is obtained ina yield of 81%: Yellowish crystals with double melting point; M.Pt 65 C.and then C.

1 3 EXAMPLE 5 Butyl- Z-amino-S-chloro-phenyl -methane-imine (43 60 CBl-phenyl-1-(2-amino'5-chloro-phenyl)-4-oxo-5-oxa-2- aza-1-heptene (4292CB) A mixture of 27.6 g. (0.12 mol) of(2-amino-5-chlorophenyl)-phenyl-methane-imine and 20.7 g. (0.15 mol) ofthe hydrochloride of ethyl glycine in 150 ml. of methanol is stirred atroom temperature for 2.5 hours. A suspension of a pale yellow solid isobtained which consists of the mixture of imine and ammonium chlorideformed in the reaction. The solvent is evaporated under reduced pressureand the residue taken up in methylene chloride. It is washed with aaqueous solution of sodium carbonate, then with water, dried over sodiumsulphate and the solvent removed by evaporation. A yellow solid remainsbehind which is crystallised from acetone. 32.4 g. of the crystallineproduct is obtained; M.Pt. 130 135 C.; yield: 85%.

This product is a mixture of the two stereoisomeric forms and may beused as it is for further reactions.

However, each of these forms can be obtained in the pure state byfractional crystallisation from acetone. They have the following meltingpoints: Chelate form: M.Pt. 148150 C., non-chelate form: M.Pt. 142- 144C.: Mixing these two forms lowers the melting point.

EXAMPLE 7 l-phenyl-1-(2-methylamino-5-chlorophenyl)-4-oxo-5-oxa-2-aza-l-heptene (4361 (CB) This compound is prepared by themethod indicated in Example 6, the(2-amino-5-chloro-phenyl)-phenylmethaneimine being replaced by thestoichiometric quantity of(Z-methylamino-5-chloro-phenyl)-phenyl-methane-imine.

On crystallisation from hexane, a solid is obtained which consists of amixture of the two stereoisomeric forms M.Pt. 70-75 C., yield: 82%.

This mixture can be used as it is for subsequent reactions. However,each of the two forms can be isolated in the pure state by fractionalcrystallisation from hexane.

The melting points of these two forms are as follows: Chelate form:M.Pt. 110 C., non-chelate form M.Pt. 85 C.

The mixture of the two forms has a considerably lower melting point.

EXAMPLE 8 Diethyl [2-phenyl-2-(2-amino-5-chlorophenyl)-1- aza-vinyl]malonate (4346 CB) A solution of 9.2 g. (0.04 mol) of(2-amono-5-chlorophenyl)-phenyl-methane-imine in 16 ml. of absolutealcohol is added dropwise to a boiling solution of 10.6 g. (0.05 mol) ofthe hydrochloride of ethyl aminomalonate in 30 ml. of absolute alcohol.When this is completed, the mixture is heated under reflux for 30minutes and the solvent is then evaported in vacuo.

The residue is taken up in water and in ether, the

ethereal solution is decanted, washed with water, dried over sodiumsulphate and the solvent evaporated. The product is recrystallised fromdiisopropyl ether. Yellow 14 crystals are obtained (7.8 g.; yield: 50%M.Pt. 106 C.).

EXAMPLE 9 Diethyl [2-phenyl-2-(Z-methylamino-5-chloro-phenyl)-1-aza-vinyl) -malonate (43 62 CB) This compound is prepared by the methodindicated in Eaxample 8, the(2-amino-5-chloro-phenyl)-phenylmethane-imine being replaced by thestoichiometric quantity of(2-methylamino-5-chloro-phenyl)-phenylmethane-imine. The product is ayellow solid M.Pt. 88 C. (isophrophyl ether). Yield: 25%.

EXAMPLE 10 l-phenyl- 1- (2-amino-phenyl) -4-oxo-5-oxa-2-aza- 1- heptene(4363 CB) This compound is obtained by the technique described inExample 6, the (2-amino-5-chloro-phenyl)-phenylmethane-imine beingreplaced by an equirnolecular quantity of(2-amino-phenyl)-phenyl-methane-imine.

The product is obtained in the form of yellowish crystals; M.Pt. 106 C.(isopropyl ether); yield: 58%.

EXAMPLE 11 Diethyl [2-phenyl-1-(2-amino-phenyl)-1-azavinyl]-malonate(4351 CB) Using the same method as described in Example 8 but replacingthe (Z-amino-S-chloro-phenyl)-phenyl-methane-mine by the equimolecularquantity of (2-aminophenyl) -phenyl-methane-imine, compound 4351 CB isobtained in a yield of 31% Pale yellow crystals are obtained; M.Pt. C.(diisopropyl ether).

It is to be noted that in this method of preparation, a small quantityof the cyclised product of 3-carbethoxy- 5-phenyl-2 oxo2,3-dihydro-1H-benzo[f]-1,4-diazepine (4352 CB) can be isolated from themother liquor in addition to the main product.

EXAMPLE 12 1-phenyl-1-(2-amino-5-methyl-phenyl) -4-oxo-5oxa-Z-aza-l-heptene (4364 CB) This product is obtained by the methoddescribed in Example 6, the (2 amino 5 chloro phenyl)-phenyLmethane-imine being replaced by the equimolecular quantity of(2-amino-5-methyl-phenyl)-phenyl-methaneimine.

Yellowish crystals; M.Pt. 131 C. (diispoprophyl ether); yield: 35%.

It should be noted that the (2-arnino-5-methyl-phenyl)-phenyl-methane-imine which was prepared by the method described inExample 1 by replacing 2-amino-5-chlorobenzonitrile by an equimolecularquantity of 2-amino-5- methyl -benzonitrile could not be obtained in thecrystalline state. The crude oily product was used in subsequentreactions including the reactions described above.

EXAMPLE 13 1-butyl-(2-amino-5-chloro-phenyl)-4-oxo-5-oxa-2-aza-1-heptene (4365 CB) This compound is prepared by the methodindicated in Example 6, substituting for (Z-amino-S-chloro-phenyl)-phenyl-rnethane-imine an equivalent quantity of butyl-(2-amino-5-chiloro-phenyl)-methane-imine. Yellow crystals are obtained;M.Pt. 96-97 C. (isoprophyl ether); yield: 55%.

EXAMPLE 14 7-chloro-5-phenyl-2-oxo-2,3-dihydro lH-benzo [f]-1,4-diazepine (A) The same procedure is employed as in Example 6 andthen, without isolating compound 4292 CB, it is taken up in ml. ofacetic acid and heated under reflux for 30 minutes. The acetic acid isevaporated until a dry 15 residue is obtained, 250 ml. of diisopropylether and 250 ml. of water are added and the mixture then stirred. Ayellowish solid separates which is dried and then washed with ether. Itis recrystallised from methyl ethyl ketone. Pale yellow crystals areobtained.

First crop 23.4 g. M.Pt. 214-2l6 C. Second crop 2.3 g. M.Pt. 214-216 C.Yield: about 80% from the unsubstituted imine. The product is identicalwith the product described by Sternbach and Reeder, Journal of OrganicChemistry 1961, volume 26, page 4936).

EXAMPLE 15 7-chloro-5-phenyl-2-oxo-2,3-dihydro 1H-benzo[t]-l-4-diazepine (A) Acetic acid is added to a solution of 0.409 g. (0.001mol) of the dipotassium salt of [2-phenyl(2-amino-5-chloro-phenyl)-1-aza-viny1]-malonic acid (4306 CB) in 4 ml. of distilledwater to adjust the solution to pH 4. The solution is heated ona waterbath for 15 minutes; a solid precipitates which which is separated,washed with water and dried; weight: 0.216 g.; M.Pt. 214216 C.; yield80%. This product is identical with the product obtained in Example 14.

EXAMPLE 1 6 7-chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (B) 6 g. of compound 4361 CB are heated underreflux for 15 minutes in 25 ml of acetic acid. The acetic acid isremoved in vacuo and the residue is taken up in Water and a littleether. A yellowish solid separates; M.Pt. 130 C.; the yield issubstantially quantitative. It is recrystallised from diisopropyl ether.Yellowish crystals are obtained (4.4 g.); M.Pt. 132 C.; yield 85% in thefirst batch. The product is identical with the known product (seereference above in Example 14).

EXAMPLE 17 7-chloro-3-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (C) A mixture of 6.9 g. (0.03 mol) of 4356 CB and51 g. (0.033 mol) of the hydrochloride of the ethyl ester of DL-alaninein 40 cc. of absolute alcohol is heated under reflux for one hour. It isevaporated to dryness and the residue taken up in methylene chloride anda 10% sodium carbonate solution. The organic layer is separated, washedwith water and dried over sodium sulphate. The solvent is evaporated andthe residue taken up in 40 cc. of acetic acid. It is heated under refluxfor minutes and the solvent then evaporated under reduced pressure.Diisopropyl ether is added and the product allowed to crystallise; clearyellow crystals are obtained (5.15 g.), M.Pt. 224 C. Yield: 60% in thefirst crop. The product is identical with that described in Journal ofOrganic Chemistry 1962, volume 27, page 3788.

EXAMPLE 18 7-chloro-3-isobutyl-5-phenyl-2-oxo-2,3-dihydro-l-H-benzo[f]-1,4-diazepine (D) The procedure is the same as described inExample 17 except that the hydrochloride of the ethyl ester of DL-alanine is replaced by the hydrochloride of the ethyl ester ofDL-leucine in equimolecular quantity. Compound (D) is obtained in ayield of 48%; M.Pt. 213 C. (ethyl acetate). The product is identicalwith the product described in the chemical literature (reference givenabove).

EXAMPLE 19 7-chloro-3- 3-thiabutyl -5-phenyl-2-oxo-2,3-dihydrolH-benzo[f]-l,4-diazepine (E) This product is obtained utilisingthe procedure described in Example 17, the hydrochloride of ethyl esterof DL-alanine being replaced by that of the ethyl ester ofDL-methionine. in excess of the theoretical quantity).

Employing the same treatment after crystallisation from ethyl acetate,7-chloro-3-(3-thiabutyl)-5-phenyl-2- oxo 2:3dihydro-lH-benzo[f]-1,4-diazepine (M.Pt. 184 C.) is obtained in a yieldof 50%. The product is identical with the product described in thechemical literature (reference given above).

EXAMPLE 20 7-chloro-3-carbethoxy-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-l,4-diazepin (4279 CB) This compound is obtained by theprocedure described in Example 16, compound 4361 CB being replaced by anequimolecular quantity of compound 4346 CB. Shiny, colourless crystalsare obtained; M.Pt. 244 C. (ethyl acetate). Yield: 74% in the firstcrop.

EXAMPLE 21 7-chloro-3-carbethoxy-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepin (4279 CB) A mixture of 9.2 g. (0.04 mol) ofcompound 4356 CB, 10.6 g. (0.05 mol) of the hydrochloride of ethylaminomalonate and 5 g. (0.05 mol) of triethylamine in 45 ml. of absoluteethyl alcohol is heated under reflux for one hour. The solvent isevaporated under reduced pressure and the residue taken up in water andether. The ethereal layer is separated, washed with water and dried oversodium sulphate. After evaporation of the solvent, the residue isdissolved in 45 ml. of acetic acid and heated under reflux for 15minutes. The product is evaporated to dryness under reduced pressure andtaken up in ether. A solid separates which is filtered by suction andrecrystallised from ethyl acetate. Brilliant, colourless crystals areobtained (6.4 g.) M.Pt. 244 0.; yield: 47%. The product is identicalwith that obtained in Example 20.

EXAMPLE 22 7-chloro-3-methoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-lH-benzo[f]-1,4-diazepine (4347 CB) A solution of 9.2 g. (0.04mol) of compound 4356 CB in 20 ml. of methanol is added dropwise, in thecourse of one hour 30 minutes, to a boiling solution of 9.2 g. (0.05mol) of the hydrochloride of methyl aminomalonate in 30 ml. of methanol.When this is completed, heating under reflux is continued for 30 minutesand the product then concentrated to dryness under reduced pressure. Theresidue is taken up in water and ether, the ethereal layer separated,the product washed with water and dried over sodium sulphate. Thesolvent is evaporated under reduced pressure. The residue, whichconsists of the methyl ester homologous with the ethyl ester describedin Example 6, could not be obtained in the crystalline state. It isdissolved in 25 ml. of acetic acid, heated under reflux for 15 minutes,the product evaporated to dryness and the residual oil taken up inether. A colourless solid separates which is filtered by suction andrecrystallised from methanol. Colourless crystals are obtained (4.7 g.);M.Pt. 226 C. A second crop (1.5 g.) is obtained on concentration of themother liquor; M.Pt. 222 C.; total quantity 6.2 g., corresponding to ayield of 47%.

EXAMPLE 23 7-chloro-3-carbethoxy-1-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-benzo[f]-1,4-diazepine (4366 CB) This product is prepared bythe method described in Example 22, the methyl aminomalonate andcompound 4356 CB being respectively replaced by ethyl aminomalonate andcompound 4357 CB in equimolecular quantities. Light yellow crystals areobtained; M.Pt. 180 C. (ethyl alcohol); yield: 47%.

17 EXAMPLE 247-chlo1'o-3-carbamoyl-5-phenyl-2-oxo-2,3-dihydrolH-benzo[f]-l,4-diazepine(4348' CB) EXAMPLE 25 7-chloro-3-methylaminocarbonyl-5-phenyl-2-oxo-2,3-dihydro-lH-benzo [f]-1,4-diazepine (43 67 CB) This product is preparedby the method of Example 24, the solution of ammonia in methanol beingreplaced by the equivalent quantity of a solution of monomethylamine inmethanol. Colourless crystals are obtained (ethyl alcohol); M. Pt. 294C.; yield: 90%.

EXAMPLE 26 7-chloro-3-dimethylaminocarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (4368 CB) This compound is obtained asin Example 24, the solution of ammonia in methanol being replaced by theequivalent quantity of a solution of dimethylamine in methanol.Colourless crystals are obtained; M.Pt. 297 C.

EXAMPLE 27 7 chloro 3 (2-diethylamino-ethylaminocarbonyl) phenyl 2 oxo2,3 dihydro 1H[f] 1,4 diazepine (4369 CB) This compound is obtained bythe procedure employed in Example 24, the solution of ammonia inmethanol being replaced by a solution of 2-diethylamino-ethylamine(three times the calculated quantity) in times its volume of methanol.Colourless crystals are obtained; M.Pt. 220 C. (ethyl acetate); yield:90%.

EXAMPLE 28 3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-l,4-diazepine (4352 CB) This compound is obtained by the methodemployed in Example 16, compound 4361 CB being replaced by anequimolecular quantity of compound 4351 CB. Colourless crystals areobtained; M.Pt. 226 C. (ethyl acetate); yield: 70% in the first crop.

EXAMPLE 29 7-methyl-5-phenyl-2-oxo-2,3 -dihydrolH-benzo[f] 1,4-diazepine (F) The procedure described in Example 14 is employed,compound 4292 CB being replaced by an equivalent quantity of compound4364 CB.

Yellowish crystals are obtained; M.Pt. 208 C. (ethyl acetate); yield44%. This product is identical with that described in the literature(see reference in Example 17).

EXAMPLE 7 -methyl-3-ethoxycarbonyl-5 -phenyl-2-oxo-2,3-dihydrolH-benzo[f]-l,4-diazepine (4327 CB) This compound is obtained by the proceduredescribed in Example 22, the hydrochloride of methylaminomalonate andcompound 4356 CB being replaced by the equivalent quantities of,respectively, the hydrochloride of ethyl 18 aminomalonate and(2-amino-5-methyl-phenyl)-phenylmethane-imine prepared according toExample 12.

Yellowish crystals are obtained; M.Pt. 260 C.; yield 25%.

EXAMPLE 31 7-nitro-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydrolH-benzo[f] -l,4-diazepine (435 3 CB) 12.3 g. (0.04 mol) of the finely powderedcompound 4352 CB are added slowly, with stirring, to 50 ml. ofconcentrated sulphuric acid (66 B.) in such a manner that thetemperature does not rise above 25 C. 4.8 g. (0.048 mol) of powderedpotassium nitrate is then gradually added to the resulting solution at arate such that the temperature remains below 25 C. When this iscompleted, the mixture is stirred for 2 hours 30 minutes at roomtemperature. The reaction mixture is then poured on to a mixture ofcrushed ice and ether and allowed to stand for 0.5 hour. The solid whichseparates is filtered by suction, Washed with water and with ether. Itis recrystallised from a large volume of ethyl acetate. Pale yellowcrystals are obtained (7.7 g.); M.Pt. 271 C.; yield: 55%.

EXAMPLE 32 7-amino-3-ethoxycarbonyl-S-phenyl-Z-oxo-Z 3-dihydrolH-benzo[f]-l,4-diazepine (4354 CB) A solution of 4.48 g. (0.0133 mol) ofcompound 4353 CB dissolved in ml. of dimethylformamide and 120 ml. ofethyl alcohol is hydrogenated at ordinary tempera ture and pressure inthe presence of Raney nickel. The theoretical absorption of hydrogenrequires about 3 hours.

After filtration of the catalyst and evaporation of the solvents underreduced pressure, a solid residue is obtained which is recrystallisedfrom a mixture of dimethylformamide and ethyl alcohol. Pale yellowcrystals are obtained (3.9 g.); M.Pt. 305 C. (decomposition); yield:

EXAMPLE 33 7-chloro-5-cyclohexyl-2-oxo-2,3-dihydro-lH-benzo [f]1,4-diazepine (4190 CB) This product is prepared by the proceduredescribed in Example 17, compound 4356 CB and the hydrochloride of theethyl ester of DL-alanine being respectively replaced by equimolecularquantities of compound 4359 CB and the hydrochloride of ethyl glycine.Yellowish crystals are obtained; M.Pt. 210 C. (n-propyl alcohol); yield:71% from the imine. In this case, the intermediate product viz.1-cyclohexyl-1-(2-amino-5'-chloro-phenyl)-4-oxo- 5-oxa-2-aza-1-heptenecould not be isolated in the crystalline state.

EXAMPLE 34 7-chloro-3-ethoxycarbonyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-benzo [f]-1,4-diazepine (4370 CB) This product is prepared bythe procedure described in Example 22, methyl aminomalonate and compound4356 CB being respectively replaced by the stoichiometric quantities ofethyl aminomalonate and compound 4359 CB.

Colourless crystals are obtained, M.Pt. 208 C. (ethyl acetate); yield:40%. It should be noted that in this case, the intermediate diethyl[2-cyclohexyl-2-(2-amino-5-chlorophenyl)-1-azavinyl]-malonate could notbe isolated in the crystalline state.

EXAMPLE 35 Dipotassium salt of[2-phenyl-2-(2-amino-5-chlorophenyl)-l-aza-vinyl]-malonic acid (4306 CB)50 g. of caustic potash are dissolved in 1350 ml. of 96% ethyl alcohol,and 82 g. (0.25 mol) of compound 4347 CB are then added all at once at atemperature of about 70 C.

The solid dissolves rapidly to form a yellow solution which then losescolour whilst simultaneously an abundant colourless precipitate appears.

After cooling, the solid is filtered by suction and washed with alcoholat 96 C. The product is dried at ordinary temperature in a high vacuum.A colourless solid is obtained (quantitative yield), which is completelysoluble in water. The aqueous solution is strongly alkaline in reaction;when acidified with acetic acid and heated on a water bath, it yields aprecipitate of 7-chloro-5-phenyl-2- oxo-2,3-dihydro-1H-benzo[f]-1,4,diazepine (compound A).

Comments:

(1) The preparation may be carried out by replacing compound 4347 CB bythe corresponding ethyl ester (4279 CB). A similar yield of compound4306 CB is obtained.

(2) The corresponding disodium salt can be obtained in the same mannerby replacing potassium hydroxide by sodium hydroxide.

EXAMPLE 36 Dipotassium salt of[2-phenyl-2-(2-amino-5-chlorophenyl)-1-aza-vinyl]-malonic acid (4306) 2g. of 4346 CB are added to a solution of 0.84 g. (0.015 mol) ofpotassium hydroxide in 1 ml. of water and 25 ml. of methanol and themixture then heated to reflux. The solid dissolves, giving rise to a redsolution which rapidly loses its colour, a precipitate appearing at thesame time. After cooling, the solid is filtered by suction and washedwith methanol. A colourless solid is obtained (1.25 g.). This compoundis found to be identical with that prepared in Example 35.

EXAMPLE 37 Dipotassium salt of[2-phenyl-2-(2-methylamino-5-chlorophenyl)-1-aza-vinyl]-malonic acid(4350 CB, first preparation) This product is obtained by the methoddescribed in Example 35, compound 4347 CB being replaced by astoichiometric quantity of compound 4366 CB. It is a colourless powderwhich is very soluble in water. Yield: 71%. The aqueous solution isstrongly alkaline in reaction.

EXAMPLE 38 Dipotassium salt of[2-phenyl-2-(2-methylamino-5-chlorophenyl)-l-aza vinyl]-malonic acid(4350, second preparation) The compound may be obtained as described inExample 36, compound 4346 CB being replaced by an equimolecular quantityof compound 4362 CB. It is a colourless powder completely soluble inwater and identical with the product of Example 37; yield: 50%.

EXAMPLE 39 Dipotassium salt of [2-phenyl-2-(Z-amino-phenyl)-1-aza-vinylJ-malonic acid (4337 CB) This substance is prepared by themethod described in Example 35, compound 4347 CB being replaced by astoichiometric quantity of compound 4352 CB.

Colourless leaflets are obtained which are completely soluble in waterand strongly alkaline in reaction; substantially quantitative yield.

EXAMPLE 40 Dipotassium salt of[2-phenyl-2-(2-amino-5-methylphenyl)-1-aza-vinyl]-malonic acid (4339 CB)This substance is prepared by the procedure given in Example 35,compound 4347 CB being replaced by an equimolecnlar quantity of compound4327 CB. It is obtained in the form of a colourless solid completelysoluble in water. The yield is practically quantitative.

20 EXAMPLE 41 Dipotassium salt of[2-phenyl-2-(Z-amino-S-nitrophenyl)-1-aza-vinyl]-malonic acid (4335 CB)This compound is obtained by the procedure described in Example 35,compound 4347 CB being replaced by an equimolecular quantity of compound4353 CB. It is a yellow powder which dissolves completely in water andis strongly alkaline in reaction; the yield is substantiallyquantitative.

EXAMPLE 42 Dipotassium salt of [2-phenyl-2-(2,5-diamino-phenyl)- l-azavinyl]-malonic acid (4371 CB) This compound is obtained by the methoddescribed in Example 35, compound 4347 CB being replaced by astoichiometric quantity of compound 4354 CB. It is a yellow solidcompletely soluble in water and having a strongly alkaline reaction. Theyield is quantitative.

EXAMPLE 43 Potassium salt of 4-phenyl-4-(2-amino-5-chloro-phenyl)-2-carbamoyl-3-aza-3-butenoic acid (4349 CB) This product is obtained bythe method described in Example 35, compound 4347 CB being replaced byan equivalent quantity of compound 4348 CB. Fine yellow crystalscompletely soluble in water are obtained in quantitative yield:

EXAMPLE 44 Calcium salt of [2-phenyl-2-(2-amino-5-chloro-phenyl)-1-aza-vinyl]-malonic acid (4372 CB) A solution of 0.55 g. (0.00375 mol)of calcium chloride dihydrate in 5 ml. of water is added to a solutionof l g. (0.0025 mol) of the dipotassium salt of [2-phenyl-2-(2-amino-5-chloro-phenyl)-1-aza-viny1]-malonic acid (4306 CB) in 15 ml. ofwater.

A solid separates out immediately. After it has been left to stand for10 minutes, it is filtered by suction, then washed with a small quantityof water and finally dried at ordinary temperature in a high vacuum. Ayellowish white solid is obtained which is sparingly soluble in water(0.75 g.); yield:

EXAMPLE 45 Potassium salt of3-[7-chloro-5-phenyl-2-oxo-2,3-dihydrolH-benzo-[f]-1,4-diazepine]-carboxylicacid (4311 CE) 2.1 g. (0.005 mol) of 4306 CB and 0.68 g. (0.005 mol) ofmonopotassium phosphate are dissolved at room temperature in 18 ml. ofWater. Solution proceeds rapidly and then colourless platelets slowlyprecipitate. The product is filtered by suction, washed first withchilled water and then with absolute alcohol. The product is dried atroom temperature for 12 hours and then in a high vacuum. 1. 8 g. ofcolourless crystals completely soluble in water are obtained. Theaqueous solution has a substantially neutral reaction; yield: 80%. Thisproduct is decarboxylated within a few minutes by heating an aqueoussolution thereof, compound A being obtained in the crystalline state.

EXAMPLE 46 Potassium salt of 3-[5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine]-carboxylic acid (4338 CB) This compound isobtained by the procedure described in Example 45 compound 4306 CB beingreplaced by an equivalent quantity of compound 4337 CB and the volume ofwater used being reduced by one-half. It is a colourless powder whichdissolves in water, giving a substantially neutral reaction; yield: 74%.

21 EXAMPLE 47 Potassium salt of 3-[7-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine]-carboxylic acid (4373 CB) The same procedureis employed as in Example 45 but compound 4306 CB is replaced bycompound 4339 CB in stoichiometric quantity and the volume of Water usedis reduced by one-half.

It is a colourless solid completely soluble in water; yield: 45%.

EXAMPLE 48 Potassium salt of3-[7-nitro-5-phenyl-2-oxo-2,3-dihydrolH-benzo[f]l,4-diazepine]-carboxylic acid (4336 CB) This product is prepared by themethod of Example 45, compound 4306 CB being replaced by astoichiometric quantity of compound 4335 CB and the water used isreduced to one-half the volume.

It is a light yellow powder which dissolves in water to give apractically neutral solution; yield: 79%.

EXAMPLE 49 7-chloro-3-carbethoxy-S-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (4279 CB) 423.5 g. (2 mols) of the hydrochlorideof ethyl aminomalonate and 1250 ml. of dry benzene are placed in areaction vessel equipped with stirrer, condenser, dropping funnel andimmersion tube for the introduction of gaseous hydrogen chloride. Thereaction mixture is heated under reflux and a solution of 460 g. (2mols) of the ketimine (4356 CB) in 1250 ml. of dry benzene is addedduring the course of 50 minutes. Precipitation of the hydrochloride ofthe ketimine (4356 CB) in the form of orangered crystals is observed tobegin at the commencement of the introduction of the ketimine. Heatingunder reflux is continued until the suspended precipitate becomesdiscoloured (ammonium chloride), which takes about 2 hours, and a rapidcurrent of gaseous hydrogen chloride is then bubbled through thereaction mixture for 2 hours while the mixture is kept boiling. Thehydrogen chloride of compound 4279 CB precipitates progressively in theform of an orange powder. The crystals (hydrochloride of 4279 CB andammonium chloride) are cooled, filtered by suction and rinsed withbenzene and ether. To liberate the base, the product is treated with asodium carbonate solution in the presence of methylene chloride. Theorganic layer is separated, dried, the solvent evaporated and theresidue treated with ether. A practically pure white product is thusobtained (441.5 g.; yield 63.5% M.Pt. =243244 C.

EXAMPLE 50' 3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (4352 CB) 423.5 g. (2 mols) of the hydrochlorideof ethyl amino- (2 mols) of (2-amino-phenyl) phenyl methane imineapparatus identical with that used in Example 49. The mixture is heatedunder reflux and a solution of 391 g. (2 mols) of (2-amino-phenyl)phenyl methane imine (4358 CB) in 1250 ml. of dry benzene is addedduring the course of 50 minutes. From the commencement of addition ofthe latter, the hydrochloride of compound 4358 CB precipitates in theform of deep red crystals. To facilitate the condensation reaction, 62.5ml. of methanol, i.e. 2.5% of the total solvent used, are added. Thereaction mixture is heated under reflux for 4 hours until decolorisationof the precipitate has occurred. The precipitate at the end of thereaction consists solely of ammonium chloride. Methanol is removed byazeotropic distillation (methanol-benzene) and a fast current of gaseoushydrogen chloride is then bubbled through the mixture for two hourswhilst the reaction mixture is kept boiling. The bydrochloride ofcompound 4352 CB progressively precipitates in the form of an orangepowder. The reaction mixture is cooled, the crystals of thehydrochloride of 4352 CB and ammonium chloride are filtered by suction,washed with benzene and with ether. To liberate the base, thehydrochloride is treated in the manner described in Example 49 for thehydrochloride of the compound 4279 CB. 416 g. of practically purecompound 4352 CB are obtained in this way. Yield: 67.5%; M.Pt. =224-225C.

EXAMPLE 51 7-chloro-5-cyclohexyl-2-oxo-2,S-dihydro-1H- benzo[f]-1,4-diazepine (4190 CB) The procedure according to Example 49 isemployed, the hydrochloride of ethyl aminomalonate being replaced by thestoichiometric quantity of the hydrochloride of ethyl glycinate,compound 4356 CB being replaced by the stoichiometric quantity ofcompound 4356 CB and benzene by an equal volume of toluene. Compound4190 CB is finally obtained by decomposition of its orange-redhydrochloride, giving a yield of 66.5%; M.Pt. =280 C.

EXAMPLE 52 Compound 4306 CB (Formulae IV-A, B and C with l a R2=C6H5:

341.5 g. (1 mol) of compound 4279 CB are added as rapidly as possible,with stirring, at 18 to 20 C. to a solution of 224 g. (4 mols) ofpotassium hydroxide in 5130 rnl. of ethyl alcohol containing 10% byvolume of water. A clear yellow solution forms after about 2 minutes.Stirring is stopped; crystallisation of compound 4306 CB begins afterseveral minutes and is accompanied by progressive decolorisation. Theproduct is filtered by suction after 4 hours, washed with absolutealcohol (500 ml.) and then dried to constant weight at 50 C. under anabsolute presure of 0.1 mm. 422 g. of yellowish white leaflets areobtained.

EXAMPLE 53 Compound 4335 CB (Formulae IVA, B and C in which 1= 2 2= s 5s= The procedure employed is that described in Example 52 but compound4279 CB is replaced by an equimolecular quantity of compound 4353 CB.The reaction follows the same course and compound 4335 CB is obtained inthe same yield as compound 4306 CB.

EXAMPLE 54 7-chloro-5-phenyl-2-oxo-2,3-dihydro-lH-benzo- [f]-1,4-diazepine (A) A suspension of 6.68 g. (0.02 mol) of compound 4279 CBin an aqueous solution of potassium hydroxide (4.5 g. of potassiumhydroxide in 45 ml. of water) is heated with stirring on a water bathuntil completely dissolved. There is obtained a strongly yellow colouredsolution which clears after a few minutes. The hot solution is treatedwith 6 ml. of acetic acid which causes a pasty product to separateaccompanied by evolution of carbon dioxide. Decarboxylation is completedby heating to reflux for a short time. After the reaction is completethe desired product crystallises; it is centrifuged, washed with waterand dried at 100 C. in vacuo. M.Pt. =2l2 C. The yield is practicallyquantitative. A pure product can be obtained by crystallisation asdescribed in Example 14.

Instead of an aqueous solution of potassium hydroxide, a solution ofpotassium hydroxide in ethyl alcohol, for example a percent by volumealcohol may be used the hot solution being treated with acetic acid asdescribed above.

EXAMPLE 55 7-chloro-1-methyl-S-phenyl-Z-oxo-Z,3-dihydro-1H- benzo- [f]-1,4-diazepine (B) An aqueous solution prepared by dissolving 7 g. ofpotassium hydroxide in 15 ml. of water is added to an aqueous solutionof 3 g. of compound 4306 CB, then 1.8 g. of dimethyl sulphate isgradually added (about 5 minutes) with stirring, care being taken thatthe temperature does not rise above 25 C. After the addition is ended,the mixture is left for 2 hours at room temperature then acidified withacetic acid. A pasty product separates which is covered with diisopropylether, and the suspension thus formed is heated to boiling for a fewminutes; evolution of carbon dioxide takes place. The product is cooled,diluted with ether and the aqueous phase is separated. Upon evaporationof the solvent, there is obtained a residue which is crystallised fromdiisopropyl ether. Yield 80%; M.Pt. =132 C. The product is identicalwith the product obtained according to Example 16.

A certain number of the compounds described in the present applicationhave been studied with regard to their action on the central nervoussystem, as psycholeptics, myorelaxants and tranquillisers. In addition,the acute toxicity has been determined for a number of these compounds.

The study of certain compounds of known pharmacodynamic and clinicalactivity, such as diazepame and chlorodiazepoxide, has been undertakenunder the same experimental conditions, with the same tests and withanimals of the same origin as for the new compounds. It has thereby beenpossible to make quantitative compari sons of the activity of thedifferent compounds for the diiferent tests employed.

In the series of tests briefly described hereinafter, each compound wastested with the use of five or six scaled doses on batches of 10 or 20animals for each dose; it was thereby possible to determine withsufficient exactitude by the method of probits the 50% effective dose(ED 50), that is to say the dose for which half the animals or protectedand react in a predetermined manner according to a particular action.

TESTS EMPLOYED The following tests were employed:

(1) Traction test (mice) This consists in observing when the treatedanimals are capable of retrieving a rod grasped by the front paws only.Inability to carry this out was interpreted as a sign of myorelaxantactivity.

(2) Balance test: rotating rod (mice) This test consists in observingwhether the treated animals are capable of maintaining their balance ona horizontal rod kept in rotation.

Numerous neuroleptic compounds or tranquillisers disturb theequilibration reflex.

(3) Anti-convulsant activity (anti-pentetrazole) (mice) Pentetrazole,injected intraperitoneally in a dose of 125 mg./ kg. produces fatalconvulsions in 100% of the animals.

Certain compounds exert a protective action preventing convulsions andpermitting survival.

(4) Anti-convulsant activity (electric shock) (mice) The test consistsin determining the intensity of the electric current required to producea fatal shock in a batch of test animals.

Certain preventively administered compounds effectively protect acertain percentage of animals subjected to an electric current of anintensity which is fatal to untreated animals.

(5) Exploration test (mice) This extremely simple test consists inplacing a mouse at the centre of a floor pierced with holes and innoting how many holes the mouse explores in 5 minutes. This test iscarried out in a room in which complete silence is observed and whichcontains no person except the experimenter who is seated and still. Itappeals to the curiosity of the animals. The doses of the compoundsemployed are, however, very small and considerably less than thoserequired to impair movement. This simple test makes it possible toobserve whether the compounds assayed produce a more or less pronouncedlack of interest in the environment and it gives information which isinteresting from the clinical point of view with regard to the treatmentof anxiety and restlessness.

(6) Spontaneous motor activity in the rat and mouse and provoked motoractivity The effect of drugs on voluntary movements of animals can bestudied statistically by methods the details of which will not bediscussed here. The mouse, which is an extremely lively animal and movesabout a great deal, is particularly suitable for this type ofexperiment.

Moreover, this spontaneous mobility can be exacerbated by preventiveadministration to the animals of certain substances such as benzedrine,mescaline and ritaline.

The experimental results obtained by these methods give valuableinformation for clinical purposes with regard to the treatment ofambulatory psychomotor crises.

(7) Antistrychnine activity This test demonstrates the activity of drugsagainst a medullary excitant.

(8) Morphine excitation In the cat, morphine produces a specific stateof excitation with hallucinations which can be attenuated or suppressedby certain psycholeptic drugs.

In the mouse, the action of morphine is different but also manifested bymarked central excitation.

(9) Aggressiveness (cat/mouse) In general, 75 to of cats are aggressivewhen confronted with white mice. Psycholeptics and tranquillisers maymake the cat indifferent and sometimes even amiable to the mouse.Similarly, in the case of cats that are furious and aggressive inrelation to humans, diminution or suppression of the instinctive fearand establishment of a climate of confidence are observed.

(10) Combativeness It is possible to make a male rat aggressive towardsanother male rat enclosed in the same cage by passing an electriccurrent of more or less high voltage through the floor of the cage.

This test, like the preceding one, can obviously give information ofclinical value for the treatment of aggression diseases.

(11) Conditioning test The test used consists in educating rats to avoidan electric current passed through the floor of a cage of twocompartments when they change compartments. The animal is first warnedby a lamp which lights up in the compartment through which the currentis passing while the other is in relative darkness.

This test, which requires more or less daily training at the rate of 50times for each rat, makes it possible to follow the animals and notetheir progress. The performances realised at the end of a certain time(3 weeks to one month of training) are fairly constant, the percentageof errors made by adequately gifted subjects being less than 10 and veryoften even zero.

One would imagine that disturbances produced in these performances whichcall upon the memory of animals would be of great importance for thechoice of a new medicament. A deconditioning drug of sufficientintensity could have the result of partly depriving the patient of theidea of danger and would consequently require special surveillance ofthe sick persons.

(12) Potentiation of narcosis Most psycholeptics are hypnotics in largedoses but many of them can in small doses, without themselves producingany hypnosis, either prolong the time of sleep (3) Compound 4311 is alsohighly active but slightly obtained with a true hypnotic (for exampleabarbiturate) less so than 4306. Its activity is slightly less when adorappreciably lower the dose of barbiturate required to ministeredparenterally than when administered orally. obtain sleep. What isclaimed is:

In the attached table are summarised all the results 1. A benzodiazepinehaving the formula obtained in the dilferent tests briefly recordedabove with 5 NRz-(ho certain compounds described 1n the presentapplication, compared with various reference substances of known CHR1clinical activity. Rh

10 CR2=N TABLE VL-RECAPITULATING THE ACTIVITIES OBTAINED WITH DIFFERENTTESTS [The figures in the table indicate the 50% efiective doses inmg./kg. 811:1? the troute of administration: P per os;IP=intraperitoneal; S C=subcutaneous =m ravenous Benzedrine AcuteSpontane- Spontaneprovoked toxicity Traction Equ1l1bra- Anti-pente-Electric Exploraous motor ous motor motor (M) DL 50 (M) tron (M) trazolc(M) shock (M) tion (M) activity (B) activity (M) activity (R) Disagepame(compound 72%;(g60220 1.60 PO 4.4 PO 1.7 PO 5 PO 6 PO 25 PO 5 PO 100 PO.

so. Nor-diadzegame (com- 3.5 PO 8.6 PO 2.9 PO 9 PO 7.8 PO 50 P0 50 P0100 PO.

poun Chlordiazepoxide 201050; 80 3 P0 13 PO 5 P0 17 P0 20 PO 100 PO.4294 CB 20 PO 20 PO 20 PO 100 PO 100 PO 4279 CB 8 PO 50 PO PO. 25 PO 25PO 100 PO. 4369 CB- 25 P0".-- 50 PO r 4306 CB 70250; 250 1.10 PO 14 10-01-.. 1 7 PO 100 P0 022053 the same formula as 4306 CB but obtained bysponification of the non-cyclic intermediate (4346 CB).

IP; 450 so; 220

' IV. 4336 CB 800 PO 4337 CB 5 P0 432.2 5 10 0 4339 10 PO 10 P0----- 10PO 10 PO TABLE VI.RECAPITULATIN G THE ACTIVITIES OBTAINED WITH DIFFERENTTESTS-Continued [The figures in the table indicate the 50% effectivedoses in mgJkg. and the route of administration: PO =per 0s;IP=intraperitoneal; SC =subcutaneous; IV=intravenous1 BenzedrineMescaline Ritaline provoked provoked provoked motor motor motor Anti-Morphine Aggres- Oombat- Double box Narcotic activity activity actlvitystrychexcita- Morphine siveness iveness conditioning potentia- (M) (M)(M) nine (M) tion (M) crisis (0) (CM) (R) (R) tion (M) Dgzzepame(compound PO .2 50 P0... PO. 25 SC"-.- 25 SC 25 PO Without eflect.-. 2.5PO. Nor-diazepame (com- 20 PO 100 PO Without effect.-.

pound A). Chlordiazepoxide 1008C 100 PO 4294 CB 4279 CB 4369 CB 4306 CB20 PO 20 P0..-" 20 P0.--.. 25 PO..-.- P0... 25 SC--. 25 SC 25 PO..-Improved per- 2 PO.

formances. Ca 2053 the same formula as 4306 CB but obtained bysponification of the t non-cyclic intermediate (4346 CB). 4350 CB 4336on 25 PO 25 so 25 so. 10 PO From an examination of the figures given inthe table it is found that in which R is a hydrogen or halogen atom or atri- (l) The two para-nitro derivatives 4335 and 4336, fluoromethyl,lower alkyl, lower alkoxy, nitro or amino are extremely active indifferent tests, especially as group, R is a furyl, a thienyl,cyclohexyl, lower alkyl or myorelaxants and an anticonvulsants in thetest for curia phenyl group which may be substituted by a halogen osity;on the other hand, they appear to have less effect atom or by atrifluoromethyl, nitro, lower alkoxy or lower on the faculties ofdisplacement. Lastly, they have a alkyl group, and R is a hydrogen atomor a lower alkyl marked effect in dirnnishing aggressiveness (test forcomgroup, and R is a lower carbalkoxy, carbamoyl, a N- bativeness).loweralkylcarbamoyl, a N,N-diloweralkylcarbamoyl, a N- -(2) The compound4306, very similar to 4335, is also (diloweral'kylaminoalkyl) carbamoyl,a group having the highly active and in most of the tests it is at leastequal formula COOCat in which Cat is a cation of an alkali andfrequently superior to diazepame. metal or a semication of an alkalineearth metal.

2. A process for producing a benzodiazepine having the formula NRa-C O ICHR4 R1- CRz=N in which R R and R are as defined in claim 1 and R is ahydrogen atom, a lower carbalkoxy, a carbamoyl, a N-loweralkylcarbamoyl,a N,N-diloweralkylcarbamoyl, a N-(diloweralkylaminoalkyl)carbamoyl (analkyl or substituted alkyl group, or a group having the general formulaCOOCat in which Cat is the cation of an alkali metal or the semicationof an alkaline earth metal, which comprises treating anortho-aminoarylketimine having the formula R1- CR2=NCHR4-COOR5 in whichR R and R are as defined above, R is a hydrogen atom, a lowercarbalkoxy, a carbamoyl, N-loweralkylcarbamoyl, aN,N-diloweralkylcarbamoyl, a N-(diloweralkylaminoalkyl)carbamoyl, loweralkyl or, a group having the formula COOCat in which Cat is a cation ofan alkali metal or semication or an alkaline earth metal or a groupwhich, in a natural occuring a-aminocarboxylic acid, is linked to thecarbon atom carrying the a-amino group, and R is a lower alkyl group or,when R is a carbamoyl or COOCat group, a cation of an alkali metal orsemication of an alkaline earth metal, but excluding the case in whichR; is COOCat and R is Cat, with an hydrous lower aliphatic acid or withan anhydrous mineral acid, or, when R; is COOCat and R is Cat with adilute aqueous solution of an acid salt in particular potassiumdihydrogen orthophosphate in substantially equimolar proportion or witha weak acid.

3. A process according to claim 2 in which the mineral acid ishydrochloric acid gas.

4. A process according to claim 2 in which R is a hydrogen atom or amethyl group and R is a chlorine atom or a nitro group.

5. A process according to claim 2 in which R; is a lower carbalkoxygroup and the product is thereafter treated with ammonia, aloweralkylamine, a diloweralkylamine or a diloweralkylaminoalkylamine.

6. A process according to claim 2 in which R is a lower carbalkoxy groupand the product is thereafter saponified and then treated with a dilutereactive acid to effect decarboxylation.

7. A process according to claim 2 in which R is a hydrogen atom and R isa lower carbalkoxy group and the product is treated with an aqueoussolution of an alkali metal hydroxide in order to produce thecorresponding dialkali metal salt and the said dialkali metal salt isthereafter treated with an alkylating agent and then with dilute acid.

8. A process according to claim 2 in which R is a hydrogen atom and R; alower carbalkoxy, a carbamoyl, a lower N-alkylcarbamoyl, a lowerN,N-dialkylcarbamoyl or a lower N(dialkylaminoalkyl)carbamoyl group andthe product is then mono-nitrated with a nitrating agent.

9. A process according to claim 8 in which the mononitrobenzodiazepineis reduced with a reagent known to be capable of reducing an aromaticnitro group to a primary amino group.

10. A process according to claim 2 in which R; is a lower carbalkoxygroup and the product is saponified with an alkali metal hydroxide.

11. A process for the preparation of saponification products of abenzodiazepine having the formula wherein R R and R are as defined inclaim 1, and Alk is a lower alkyl group which process comprises treatingsaid benzodiazepine with an alkali metal hydroxide in solution in alower alkanol.

12. A process according to claim 2 wherein the orthoamino aryl ketimineis the dipotassium salt of [Z-phenyl-2-(2-amino-5-chlorophenyl)1-aza-vinyl] malonic acid and the otherreactant is potassium dihydrogen orthophosphate.

13. A process according to claim 2 wherein the orthoamino aryl ketimineis the dipotassium salt of [2-phenyl- 2-(2.-'-amino-5'-nitrophenyl)-1-aza-vinyl] malonic acid and the other reactant is potassiumdihydrogen orthophosphate.

14. The potassium salt of 3-[7-chloro-5-phenyl-2-oxo-2,3-dihydro-lH-benzo[f]-1,4-diazepine]carboxylic acid.

15. The potassium salt of 3-[7-nitro-5-phenyl-2-oxo-2,3-dihydrolH-benzo- [f -1,4-diazepine] carboxylic acid.

References Cited UNITED STATES PATENTS 3,410,844 11/1968 MoCawlly260239.3

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl.X.R.

